Alzheimer's disease (AD) is the most common form of dementia in the elderly and is characterized by distinct neuropathological lesions, including senile plaques and neurofibrillary tangles that are used to confirm the diagnosis of AD. The development of APP transgenic (APP/Tg) mice that develop AD-like Abeta plaques provide powerful experimental models in which to test hypotheses on the mechanisms underlying the onset and the progression of AD, as well as potential therapeutic approaches. Immunization of APP/Tg mice with fibrillar Abeta42 induces anti- Abeta antibodies that block deposition and promoted clearance of existing Aa deposits in the APP/Tg mouse brain. In addition, immunization with Ap appears to protect mice from behavioral deficits that occur in aging APP/Tg mice. The failure of the first clinical trial has encouraged us to pursue alternative immunization strategies using Abeta as an immunogen and "molecular adjutants" that utilize the innate immune system to amplify and target the immune response against Ap. We have adopted a fourfold strategy (4 Aims) for developing a safe and effective Abeta immunotherapy: 1) To reduce the probability of generating non-functional auto-antibodies that may contribute to an adverse immune response and to generate potentially therapeutic antibodies, we propose to prepare chimeric immunogens that possess self-B, but non-self T cell epitope of Abeta42; 2) To eliminate the possibility of generation of auto-reactive T cells and to provide adequate T cell help for antibody production, we propose to remove the self- Abeta T cell epitope and engineer a promiscuous foreign T cell epitope into the chimeric immunogen; 3) To further avoid the possibility of generation of potentially dangerous Th-1 mediated proinflammatory responses and to polarize T cell response towards Th-2 phenotype, we propose to use molecular adjutants derived from the components of the innate immune system; 4) To generate potent anti-a-amyloid antibodies in APP/Tg mice, we propose to immunize novel 3xTg-AD, as well as Tg-SwDI mice with protein, DNA or a combination of these vaccines composed of 2 copies of the strong self-B cell epitope of Abeta42 (2 Aa1-11) and the strong promiscuous foreign T cell epitope, PADRE. We believe that this approach will provide a more comprehensive assessment of the overall efficacy of immunotherapy as a potential clinical approach for treating AD. [unreadable] [unreadable]